HYDROGEN PEROXIDE AND RETINAL NEUROTRANSMITTER RELEASE

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DESCRIPTION (Applicant's Description): The reactive oxygen metabolite, hydrogen peroxide (H2O2) is present in the vitreous humor, neural retina and pigment epithelium of some mammalian species. Although oxidative stress has been implicated in some retinal disorders such as age-related macular degeneration and diabetic retinopathy, no study has addressed the potential pharmacological or toxicological effect of H2O2 on the release of neurotransmitters in this tissue. These studies are needed because we have evidence that H2O2 can alter the release of norepinephrine from sympathetic nerves in the anterior uvea of several mammalian species. Furthermore, H2O2 has been reported to alter the release of dopamine and glutamate in the brain. In the present study, we will test the hypothesis that oxidative stress induced by H2O2 can modify the output of dopamine and glutamate from mammalian retinal neurons. The overall objective of the present study is to investigate the effect of H2O2 on the release of dopamine and glutamate from the retina both in vitro and in vivo. Experiments in the present project have, therefore, been designed to answer the following questions: (i) does H2O2 alter the release and/or availability of dopamine and glutamate from mammalian retina of several species? What is the role of presynaptic autoreceptors in the effects caused by H2O2? (ii) are second messengers such as calcium, cyclic nucleotides and arachidonic acid metabolites involved in the effects caused by H202 on dopaminergic and glutaminergic transmission? (iii) will an increase in the concentration of H2O2 in the vitreous humor alter the endogenous levels of dopamine and glutamate in the retina? (iv) will the inhibition of catalase activity increase the concentration of endogenous H2O2 in the eye, which in turn will alter the levels of dopamine and glutamate in the retina? (v) does biochemical change induced by intravitreally-administered H2O2 correlate with morphological alterations of retinal tissues by this oxidant? We anticipate that the results of the present study will improve our understanding of the basic mechanisms involved in the effects of H2O2 on retinal dopaminergic and glutaminergic transmission. Furthermore, we hope that the findings of this project will be applicable to diseases of the retina associated with oxidative stress such as ischemia, diabetic retinopathy and age-related macular degeneration.